As the primary mechanism by which animals detect nutrient-rich foods and discriminate against toxins, the sense of taste has a significant impact on health and behavior. Bitter tastes are perceived with high sensitivity and broad specificity, and can evoke strong aversive reactions that influence health-related behaviors such as dietary preference and pharmaceutical compliance. Conversely, sweet taste facilitates the detection and consumption of high carbohydrate (and hence highly caloric) foods, but over-consumption of calories can lead to obesity and diabetes. It is therefore desirable in many circumstances to manipulate taste perception and/or to provide taste substitutes. Bitter, sweet, and umami (savory) tastes are detected at the cellular level by a family of taste receptors (TASRs), which belong to the G protein-coupled receptor (GPCR) superfamily of proteins. Because they are refractory to direct structural visualization such as x-ray crystallography, very little is known about the structural features of TASRs that are responsible for binding ligands. Elucidating TASR-ligand structural interactions could enable the development of health-related products, such as bitter blockers and sugar substitutes. The results of this proposal would enable ligands of TASRs, and possibly other GPCRs, to be developed. PUBLIC HEALTH RELEVANCE: Taste ligands are currently used to mask aversive tastes, improve patient compliance, influence choice of foods, and modify caloric intake, so routinely influence daily human activity. This proposal will contribute to human health by using a research platform to discover novel taste ligands.